Neurodegenerative disease is among the greatest unmet challenges being faced in healthcare today. Such disease is devastating to families and an enormous economic burden. These disorders include Alzheimer's disease, Parkinson's disease, and the clinically- and pathologically-related disorders frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Despite tremendous medical advances that have extended lifespan, degenerative disease remains formidable with a huge impact on healthspan. Novel approaches and innovative applications are needed to provide biological insight into these diseases and the foundation for therapeutic advances. Drosophila melanogaster is a remarkable model organism with biological pathways highly conserved to humans, a complex brain and nervous system, and a staggering array of genetic and molecular biological approaches for gene and pathway discovery and manipulation. We propose to apply the power of Drosophila to understand genes and mechanisms that underlie neurodegenerative disease. Our special current focus is on the genetic and biological underpinnings of ALS/FTD. ALS is a devastating motor neuron disease that leads to rapid paralysis and death. FTD is the second most common form of dementia. Drosophila research has already provided many striking insights into the biological mechanisms of these diseases, while more basic insights are still needed. We have developed, and will continue to develop, models for familial disease. Our unique, interdisciplinary approach launches from a fly model, which we use to identify pathways of interest by performing genetics screens for modifiers of the disease toxicity. We then extend the findings from Drosophila into human patient tissue, mammalian cells, and primary neurons in culture, ultimately returning our in vivo fly model for detailed mechanistic insight. In addition to genetic studies, we currently plan on using the fly to assess the impact of critical risk factors, such as traumatic brain damage and the gut microbiota, the impacts of which can be difficult, or impossible, to interrogate in mammalian models or cells. Thus, launching from Drosophila, our research program strives to provide novel avenues for the understanding of disease and the foundation for therapeutic insight toward the enormous burden of neurodegenerative disease facing society today.